Prevention of Autoimmune Destruction and Rejection of Human Pancreatic Islets Following Transplantation for Insulin Dependent Diabetes Mellitus

The primary objective of these studies is to assess the efficacy and safety of allogeneic
pancreatic islet transplantation in the treatment of type I diabetes mellitus. A secondary
study objective is to evaluate the efficacy of various immunosuppressive protocols and agents
in preventing autoimmune destruction and rejection of allogeneic islet transplants. A
tertiary objective is to determine the safety and efficacy of allogeneic pancreatic islet
transplantation in patients who have received another organ transplant such as a kidney or
liver.

Inclusion Criteria:

- Type 1 Diabetes

- Metabolic lability/instability characterized by hypoglycemia or ketoacidosis(>2
hospital admissions in the previous year), erratic glucose profiles(MAGE >120mg/dL),
or disruption in lifestyle(danger to life, self or others). Reduced awareness of
hypoglycemia or > 1 episode in the last 1.5 years of severe hypoglycemia.

- Persistently poor glucose control (as defined by HgbA1c>10% at the end of six months
of intensive management efforts with diabetes care team.

- Progressive secondary complications as defined by

- a new diagnosis by an ophthalmologist of proliferative retinopathy or clinically
significant macular edema or therapy with photocoagulation during the last year;
or

- urinary albumin excretion rate >300mg/day but proteinuria <3g/day; or

- symptomatic autonomic neuropathy (as defined by postural hypotension in the
setting of euvolemia, gastroparesis or diarrhea attributed to diabetic
neuropathy, or neuropathic bladder as diagnosed by an urologist)

Exclusion Criteria:

- Patient weighs more than 80kg or body mass index BMI>28

- Patient's insulin requirement is >55 Units/day.

- Current use of immunosuppressive agents.

- History of malignancy within 10 years (except for adequately treated basal or squamous
cell CA of the skin).

- Active peptic ulcer disease.

- Severe unremitting diarrhea or other GI disorders potentially interfering with the
ability to absorb oral medications.

- Untreated proliferative retinopathy.

- Pregnancy or breastfeeding.

- Female subjects not post-menopausal or surgically sterile, or not using an acceptable
method or contraception.

- Active infections.

- Major ongoing psychiatric illness.

- Ongoing substance abuse, drug or alcohol; or recent history of noncompliance.

- Portal hypertension or history of significant liver disease.

- Lymphopenia (<1000/ul) or leukopenia (<3000 total leukocytes/ul) or an absolute CD4
count <500/ul.

- Presence or history of panel-reactive anti-HLA antibody >20%.

- Evidence of acute EBV infection (IgM>IgG) OR no serologic evidence of previous
exposure to EBV (IgG>IgM).

- Serologic evidence of infection with HIV or HbsAg or HCV Ab positive.

- Creatinine clearance <60ml/min/m2.

- Positive lymphocytoxic cross-match using donor lymphocytes and serum